The broad goals of our project are to pharmacologically optimize, mechanistically characterize (in the most appropriate molecular, cellular and transgenic animal models) and complete the entire preclinical development (through IND filing) of a potent orally bioavailable therapeutic compound carefully selected from a novel series of recently discovered gamma-secretase modulators (GSMs) for the treatment of Alzheimer's disease (AD). AD is neurodegenerative disorder that affects regions of the brain associated with learning and memory. AD affects over 24 million people world-wide and is an enormous burden to society. The extent at which it will affect our aging population will continue to escalate. A recently discovered a series of aryl 2-aminothiazole gamma-secretase modulators (AGSMs) that are pharmaceutical-like small organic molecules that are able to lower Abeta42 production without measurably affecting -Secretase-mediated enzymatic processing of other known gamma-secretase substrates such as the Notch-1 receptor. This project will focus on the pharmacological optimization of a series of AGSMs with improved physicochemical properties known as SGSMs. If successful in a number of predictive preclinical studies, these molecules will undergo further IND-enabling preclinical development and ultimately be tested in humans.